@article {937, title = {Human NK cell deficiency as a result of biallelic mutations in MCM10.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 10 01}, pages = {5272-5286}, abstract = {

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

}, keywords = {Alleles, Cell Cycle Checkpoints, Cell Differentiation, Cell Line, Codon, Nonsense, DNA Damage, Fatal Outcome, Female, Gene Knockdown Techniques, Heterozygote, Humans, Induced Pluripotent Stem Cells, Infant, Killer Cells, Natural, Male, Minichromosome Maintenance Proteins, Models, Immunological, Mutation, Mutation, Missense, Pedigree, Primary Immunodeficiency Diseases}, issn = {1558-8238}, doi = {10.1172/JCI134966}, author = {Mace, Emily M and Paust, Silke and Conte, Matilde I and Baxley, Ryan M and Schmit, Megan M and Patil, Sagar L and Guilz, Nicole C and Mukherjee, Malini and Pezzi, Ashley E and Chmielowiec, Jolanta and Tatineni, Swetha and Chinn, Ivan K and Akdemir, Zeynep Coban and Jhangiani, Shalini N and Muzny, Donna M and Stray-Pedersen, Asbj{\o}rg and Bradley, Rachel E and Moody, Mo and Connor, Philip P and Heaps, Adrian G and Steward, Colin and Banerjee, Pinaki P and Gibbs, Richard A and Borowiak, Malgorzata and Lupski, James R and Jolles, Stephen and Bielinsky, Anja K and Orange, Jordan S} } @article {473, title = {Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1126-1142}, abstract = {

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that~perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in~any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune~phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

}, keywords = {Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.010}, author = {Poli, M Cecilia and Ebstein, Fr{\'e}d{\'e}ric and Nicholas, Sarah K and de Guzman, Marietta M and Forbes, Lisa R and Chinn, Ivan K and Mace, Emily M and Vogel, Tiphanie P and Carisey, Alexandre F and Benavides, Felipe and Coban-Akdemir, Zeynep H and Gibbs, Richard A and Jhangiani, Shalini N and Muzny, Donna M and Carvalho, Claudia M B and Schady, Deborah A and Jain, Mahim and Rosenfeld, Jill A and Emrick, Lisa and Lewis, Richard A and Lee, Brendan and Zieba, Barbara A and K{\"u}ry, S{\'e}bastien and Kr{\"u}ger, Elke and Lupski, James R and Bostwick, Bret L and Orange, Jordan S} } @article {230, title = {Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy.}, journal = {J Clin Immunol}, volume = {34}, year = {2014}, month = {2014 Oct}, pages = {871-90}, abstract = {

PURPOSE: Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T(-)B(+)NK(+)severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred.

METHODS: We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings.

RESULTS: We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA(+) (na{\"\i}ve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations.

CONCLUSION: We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal na{\"\i}ve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.

}, keywords = {Adolescent, B-Lymphocytes, CD4-Positive T-Lymphocytes, Child, DNA Mutational Analysis, Epidermodysplasia Verruciformis, Female, Genetic Predisposition to Disease, Granuloma, Heterozygote, Humans, Immunologic Memory, Killer Cells, Natural, Leprosy, Tuberculoid, Male, Microfilament Proteins, Molluscum Contagiosum, Mucous Membrane, Mutation, Papillomavirus Infections, Polymorphism, Genetic, Severe Combined Immunodeficiency, Siblings, Skin, Telomere Shortening}, issn = {1573-2592}, doi = {10.1007/s10875-014-0074-8}, author = {Stray-Pedersen, Asbjorg and Jouanguy, Emmanuelle and Crequer, Amandine and Bertuch, Alison A and Brown, Betty S and Jhangiani, Shalini N and Muzny, Donna M and Gambin, Tomasz and Sorte, Hanne and Sasa, Ghadir and Metry, Denise and Campbell, Judith and Sockrider, Marianna M and Dishop, Megan K and Scollard, David M and Gibbs, Richard A and Mace, Emily M and Orange, Jordan S and Lupski, James R and Casanova, Jean-Laurent and Noroski, Lenora M} }